MECHANISMS OF CIRCADIAN CLOCK OUTPUT

昼夜节律时钟输出机制

基本信息

批准号：
10322450
负责人：
Paul H Taghert
金额：
$ 29.88万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10322450
关键词：
Activity Cycles Address Behavior Behavioral Brain Brain imaging Brain scan C-terminal Calcium Cause of Death Cell Communication Cells Complex Data Analyses Disease Drosophila genus Elements Exhibits Foundations Frequencies Genes Genetic Goals Heart Arrest Image In Vitro Individual Jet Lag Syndrome Learning Lighting Link Locomotion Maps Mediating Methods Modernization Modification Molecular Nature Neuronal Plasticity Neurons Neuropeptides Neurosciences Organ Output Pacemakers Pattern Periodicity Personal Satisfaction Phase Phosphorylation Site Physiological Physiology Positioning Attribute Property Psyche structure Publishing Receptor Signaling Regulation Research Research Proposals Rest Sampling Scanning Signal Transduction Sleep Stroke Structure System Testing Time Variant Work brain behavior circadian circadian biology circadian pacemaker fly genetic regulatory protein in vivo infancy innovation interest neural circuit neuronal circuitry neuronal patterning nodal myocyte programs promoter receptor relating to nervous system shift work theories

项目摘要

In this proposal, I outline a set of three related yet independent studies of circadian neural output. Recent advances in imaging and data analysis capture information regarding network phenomena with increasing spatial and temporal precision. The circadian pacemaker system we study is advantageous in that it produces physiological activity both spontaneously and rhythmically. In the previous cycle, we used planar illumination methods to perform 24 hr in vivo brain-wide scans of the circadian neural circuit. That work introduced a new concept to theories of how the circadian network encodes time: we showed that the molecularly synchronous pacemaker network displays sequential activation by different identified pacemaker groups across the day. Further we found pacemaker cell interactions, in the form of neuropeptide-mediated delay, represents a key mechanism to effect sequential pacemaker activation. The scientific premise for this project rests on the need to extend those observations on circadian pacemaker neuronal plasticity and to understand how these activity patterns are transmitted to downstream centers. Here I propose work that continues real-time in vivo studies of neuronal activity patterns for the core Drosophila circadian pacemaker neurons. It also continues the focused analysis of neuropeptide modulatory mechanisms that critically regulate the specific timing of pacemaker activity. To extend the scope of our initial studies, and to provide a better understanding of neuronal properties of pacemakers and pacemaking networks, this program will pursue three Aims. Aim 1 will better define daily Ca2+ dynamics in pacemakers by (i) performing in-depth, high frequency sampling, and (ii) by determining the sub-cellular mechanisms underlying these fluctuations. Aim 2 will pursue a Structure-Function analysis of the PDF receptor (PDFR), especially its C-terminus, to understand the regulatory mechanisms that control the quantitative extent of daily PDF signaling. It also seeks to identify key PDFR regulatory proteins. Aim 3 seeks to extend the scope of our work beyond the circadian pacemaker network to identify downstream circuit elements: we will focus on subsets of neurons in the Central Complex for which preliminary evidence suggests an involvement in daily rhythmic physiology associated with locomotion. Jet-lag, shift-work and disturbances in sleep-activity cycles all contribute to degrade mental and physical well-being. Two major causes of death (stroke and cardiac arrest) display clear time- of-day variation, yet, we have little understanding of the causal links between circadian clock functions and disease mechanisms. This research program is dedicated to a better understanding of fundamental circadian output mechanisms.

在此提案中，我概述了三个相关但独立研究的昼夜研究输出。成像和数据分析的最新进展捕获有关网络的信息现象具有增加的空间和时间精度。昼夜节律制作系统我们研究是有利的，因为它会自发产生生理活性和节奏。在上一个周期中，我们使用平面照明方法在体内执行24小时大脑扫描昼夜节律。这项工作向昼夜节律如何编码时间的理论：我们表明该分子是同步起搏器网络通过不同的识别显示顺序激活起搏器集团全天。此外，我们以形式发现了起搏器细胞相互作用神经肽介导的延迟，代表了实现顺序起搏器的关键机制激活。该项目的科学前提是需要扩展这些项目的观察昼夜节律起搏器神经元可塑性，并了解这些活动如何模式传输到下游中心。在这里，我建议继续实时的工作核心果蝇昼夜节奏起搏器神经元活动模式的体内研究神经元。它还继续对神经肽调节机制的重点分析，严格调节起搏器活动的特定时间。扩展我们最初研究的范围，并更好地了解神经元起搏器和起搏器网络的属性，该计划将追求三个目标。目的 1将更好地定义起搏器中的每日Ca2+动态，（i）深入，高频率采样，以及（ii）通过确定这些基础的亚细胞机制波动。 AIM 2将进行PDF受体（PDFR）的结构功能分析，特别是其C端，以了解控制定量的调节机制每日PDF信号的范围。它还试图识别关键的PDFR调节蛋白。目标3 寻求将我们的工作范围扩展到昼夜节律的范围之外下游电路元素：我们将重点关注中心综合体中神经元子集哪些初步证据表明参与与每日节奏生理相关的参与带有运动。睡眠活动周期中的喷气滞后，轮班工作和干扰都会导致精神降解和身体健康。两个主要的死亡原因（中风和心脏骤停）显示明确的时间 - 对于日期的变化，我们对昼夜节律之间的因果关系几乎没有理解功能和疾病机制。该研究计划致力于更好理解基本的昼夜节律产出机制。